The present invention relates to a new process for the preparation of xcex1,xcex2-unsaturated alcohols by the diasteroselective reduction of xcex1,xcex2-unsaturated ketones. Representative reactants and products of the present invention are depicted in FIG. 1, with compound (I) depicting representative product xcex1,xcex2-unsaturated alcohols, compound (II) depicting representative xcex1,xcex2-unsaturated ketones, and compound (III) depicting representative epimers of product xcex1,xcex2-unsaturated alcohols (I).
xcex1,xcex2-Unsaturated alcohols of general formula (I) are important key intermediates of prostaglandine derivatives used in veterinary and human medicine.
The synthesis of these compounds is carried out most frequently by reduction of xcex1,xcex2-unsaturated ketones of formula (II), when a mixture of xcex1,xcex2-unsaturated alcohols of formula (I) and the epimers of formula (III): 
is formed. These two epimer alcohols are separated directly or during some further steps of chemical transformation, usually by chormatographic.
The synthesis of these compounds is carried out most frequently by reduction of xcex1,xcex2-unsaturated ketones of formula (II), when a mixture of xcex1,xcex2-unsaturated alcohols of formula (I) and their epimers of formula (III):
The reduction of the keto group of xcex1,xcex2-unsaturated ketones of general formula (II) was studied in detail in order to enhance the yield and ratio of xcex1,xcex2-unsaturated alcohols of general formula (I) and at the same time to avoid saturation of the xcex1,xcex2-double bond. In the prior art the reduction of xcex1,xcex2-unsaturated ketones of general formula (II) was realized by using borohydride reagents containing a bulky, possibly optically active substituent and in a solvent having ether character (e.g. in tetrahydrofurane, or in a mixture of tetrahydrofurane, diethyl-ether and pentane), at a temperature from xe2x88x9278xc2x0 C. to xe2x88x92130xc2x0 C., where the ratio of xcex1,xcex2-unsaturated epimer alcohols of general formula (I) and of general formula (III) is altered between 1:2-4.5 (J. Am. Chem. Soc. 95, 1491 (1971); J. Am. Chem. Soc. 94, 8616 (1972); U.S. Pat. No. 3,974,183 HU-PS-175.889 Hungarian Patent ). As reducing agents commercially not available lithiumxe2x80x94diisopinocamxe2x80x94phenyl-tert-butyl-borohydride, lithium-2-thexyl-8-methyl-2-borobicyclo[3,3,1]nonyl-borohydride, lithium tricyclopentyl-borohydride or lithium-diisobutyl-tert-butyl-aluminumhydride and L-selektride(copyright) (lithium-tri-sec-butyl-borohydride) (all containing bulky groups) were used among others.
Some representatives of xcex1,xcex2-unsaturated ketons of general formula (II) were reduced by applying zinc borohydride too, in 1,2-dimethoxyethane at 0xc2x0 C. and at room temperature, where the epimers of general formula (I) and general formula (III) were formed in an 1:1 ratio (J. Am. Chem. Soc. 91, 5675 (1969); J. Am. Chem. Soc. 94, 8616 (1972); U.S. Pat. No. 3,970,684;
Using sodium borohydride in ethanol at xe2x88x9230xc2x0 C. or lithium-trialkyl-borohydride at a temperature lower than xe2x88x9290xc2x0 C. as reducing agents, the ratio of the epimeric xcex1,xcex2-unsaturated alcohols of general formula (I) and of general formula (III) fluctuated between the ratios of 50:50 and 60:40 (J. Am. Chem. Soc. 94, 8616 (1972); EP-A-435,443; EP-A-455,448; EP-A-467,564; J. Med. Chem. 24, 1353 (1981). Using sodium borohydride as reducing agent the selectivity of the reduction could be increased when the reduction was carried out at xe2x88x9278xc2x0 C. in methanol or in a mixture of methanol and dichloromethane, in the presence of cerium (III) chloride (EP-A-219,580; U.S. Pat. No. 4,739,078). Using borane as the reducing agent in the presence of 5-10% air and humidity sensitive oxazaborolydines, a far more favourable diastereomer ratio could be achieved (J. Am. Chem.Soc. 109, 7925 (1987)), but this method can not be applied on a larger scale. Using diisobutyl-aluminum-(2,6-di-tert.butyl-4-methyl phenoxide) (J. Org. Chem. 44, 1363 (1979); Bull.Chem.Soc. Japan 54, 3033 (1981)) at xe2x88x9278xc2x0 C.; aluminium-isopropoxide in nitrogen atmosphere and in hot toluene (Synthetic Communications 4, 211 (1974)), di(isobornyloxy)-aluminium-isopropoxide or other modified lithium-aluminium-hydrides (J.Am.Chem.Soc. 106, 6717 (1984); Synthetic Communications 9, 799 (1979); Synthetic Communications 9, 483 (1979)) did not represent any advantage either because of difficulties of preparing these reagents, their sensitivity, and/or the costs of preparing them.
Under the conditions of catalytic hydrogenation, e.g. using charcoal containing palladium catalyst of 5% metal content, the carbon-carbon double bond of the xcex1,xcex2-unsaturated ketons of general formula (II) saturates without the reduction of the ketone group (EP-A-289,349; Synthetic Communications 19, 245 (1989); EP-A-435,443.
It is the object of this invention to provide an industrially feasible process, which is suitable at room temperature and without applying special additives, extreme conditions and reagents for the preparation of compounds of general formula (I) by diastereomeric reduction of ketones of general formula (II) in higher yields them in any known processes. The base of this new process achieving this object is the unexpected finding that xcex1,xcex2-unsaturated alcohols of general formula (I)xe2x80x94wherein R means an alkyl group containing 1-4 carbon atoms, or in a given case benzoyl group substituted with phenyl group; R1 means hydrogen atom or an alkyl group containing 1-4 carbon atoms; R2 means hydrogen atom or alkyl group containing 1-4 carbon atoms; R3 means in a given case an alkyl group containing 1-6 carbon atoms substituted with phenyl group or with cycloalkyl group containing 5-7 carbon atoms, or in a given case phenoxy group substituted with halogen atom or a cycloalkyl group containing 5-7 carbon atoms, R4 means hydrogen atom or halogen atomxe2x80x94are formed diastereoselectively upon reduction of xcex1,xcex2-unsaturated ketones of general formula (II)xe2x80x94wherein the meanings of R, R1,R2,R3, and R4 are as given abovexe2x80x94if alkali borohydrides of small space demand are applied and the reaction is carried out in a heterogen phase, in an aprotic solvent in the presence of inorganic substances which are dissoluble in the reaction mixture and their particle sizes are small.
According to our experiences within the conditions described above and within the temperature range of xe2x88x9210xc2x0 C. and +30xc2x0 C. diastereoselectivity barely fluctuated. Thus the reaction can be carried out at about the room temperature. The term of inorganic substances dissoluble in the reaction mixture and having small particle sizes means farourably silicium compounds and/or aluminium compounds or mixtures thereof These are preferably the silica gels, different types of aluminium oxide, in the first place the xe2x80x9cactivexe2x80x9d aluminium oxides which can be acidic, basic, or neutral in their reaction, the adsorptive capacity of which can be determined by the Brockmann scale./Rxc3x6mp Chemical Encyclopedia Vol. I. p. 116-117 (Mxc3xcszaki Kxc3x6nyvkiadxc3x3=Technical Publishing House. Bp.1982)/. The term of silica gels which are useful in the claimed new process means silicic acid gels as defined in Rxc3x6mp Chemical Encyclopedia Vol.II. P. 977-978 /Mxc3xcszaki Kxc3x6nyvkiadxc3x3, Budapest. 1982/. These are for example Silica gel 60, Silica gel G. xe2x80x9cSmall particle sizesxe2x80x9d means 0.01-10000 micrometer preferably the particle size range is from 1 xcexcm to 1000 xcexcm.
Applicable aprotic solvents preferably halogenated hydrocarbons as chlorobenzene, methylene chloride, carbon tetrachloride, chloroform, 1,1,2,2-tetrachloroctane; alkane carboxylic acid esters as ethyl acetate, methyl acetate, methyl propionate; hydrocarbons as xylene, or toluene; alkyl nitriles as acetonitrile; ethers as tetrahydrofurane or diethyl-ether can be used. If we use ethanol as solvent for the reduction, or we carry out the reduction without the presence of silica gel, then diasteroeselectivity decreases substantially. The presence of small quantity of alcohol of short carbon chain e.g. methanol however facilitates the reaction.
As borohydrides of small space demand can be applied preferably their commercially available representatives sodium[trimethoxy-borohydride], lithium borohydride, sodium borohydride, potassium borohydride or sodium cyano borohydride, all of which can be used in solid or powdered form, or their aqueous or methanolic solution.
After filtering out the insoluble inorganic substance(s) particles from the reaction mixture eraporation of the filtrate a mixture of epimeric alcohols having general formula (III) and (I)xe2x80x94wherein the meanings of R, R1, R2, R3, and R4 are as given abovexe2x80x94is obtained. From this mixture the desired xcex1,xcex2-unsaturated alcohol of (general formula (I) can be isolated by applying the known separation methods for example by chromatography on a silica gel column. If desired the isolated isolated xcex1,xcex2-unsaturated alcohol of general formula (I) can be further purified by crystallization.